A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

EEG at onset and MRI predict long-term clinical outcome in Aicardi syndrome.

OBJECTIVE: Descriptions of electroencephalographic (EEG) patterns in Aicardi syndrome (AIC) have to date referred to small cohorts of up to six cases and indicated severe derangement of electrical activity in all cases. The present study was conducted to describe the long-term EEG evolution in a larger AIC cohort, followed for up to 23 years, and identify possible early predictors of the clinical and EEG outcomes. METHODS: In a retrospective study, two experienced clinical neurophysiologists systematically reviewed all EEG traces recorded in 12 AIC cases throughout their follow-up, from epilepsy onset to the present. Clinical outcome was assessed with standardized clinical outcome scales. RESULTS: Analysis of the data revealed two distinct AIC phenotypes. In addition to the "classical severe phenotype" already described in the literature, we identified a new "mild phenotype". The two phenotypes show completely different EEG features at onset of epilepsy and during its evolution, which correspond to different clinical outcomes. CONCLUSIONS: Data from our long-term EEG and clinical-neuroradiological study allowed us to describe two different phenotypes of AIC, with different imaging severity and, in particular, different EEG at onset, which tend to remain constant over time. SIGNIFICANCE: Together, these findings might help to predict long-term clinical outcomes.

Video game-induced reflex seizures via a smartphone.

Reflex seizures are consistently evoked by a specific afferent stimulus or by patient activity. Patients experiencing reflex seizures when playing a game on a mobile phone are rarely reported. We describe a boy with reflex seizures after prolonged exposure to the game, Cut the rope, on his mobile phone. The video-EEG documented electroclinical events characterized by distal myoclonic jerks of the upper limbs, in combination with irregular, diffuse spike-and-wave and polyspike-and-wave discharges on EEG, followed by a tonic-clonic seizure. Playing video games on mobile phones may potentially induce reflex seizures, similar to other commonly used platforms such as docking stations connected to video screens.

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

PURPOSE: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. METHODS: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. RESULTS: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). CONCLUSION: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.

Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature.

BACKGROUND: Extraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population. CASE PRESENTATION: We describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship. CONCLUSION: In childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit.

Pallidotomy for medically refractory status dystonicus in childhood.

AIM: Status dystonicus is a rare and potentially fatal condition of continuous and generalized muscle contraction that can complicate dystonia. As status dystonicus is usually refractory to traditional pharmacological therapy, alternative and invasive strategies have been developed, but so far there are no guidelines on status dystonicus management. Pallidotomy has shown good results in status dystonicus treatment. METHOD: We report indications, surgical strategy, and outcome of bilateral pallidotomy in four pediatric patients (four males; mean age at surgery 11y 5mo) with secondary dystonia, who developed refractory status dystonicus. Pallidotomy was performed in the area corresponding to the mid portion of the globus pallidus internus. RESULTS: This procedure allowed patients to recover the pre-status dystonicus condition, controlling dystonic postures and movements of trunk and limbs. Moreover oromandibular dystonia, which is resistant to conservative approaches and deep brain stimulation, was significantly reduced. No postoperative complications were registered. INTERPRETATION: Our study suggests pallidotomy as a feasible treatment in patients with secondary dystonia complicated by status dystonicus.

Vagus nerve stimulation for drug-resistant Epilepsia Partialis Continua: report of four cases.

BACKGROUND: Vagus nerve stimulation (VNS) represents an adjunctive surgical option for adult and pediatric patients with drug-resistant epilepsy, who are not eligible for surgical resection or disconnection. However, little is known on its efficacy in the treatment of Epilepsia Partialis Continua (EPC), a rare but serious form of motor status epilepticus associated either with progressive or with non-evolving neurological diseases. PURPOSE AND METHODS: To evaluate the effect of VNS in a series of four children affected by medically unresponsive EPC secondary to chronic inflammatory encephalopathy (two cases), Rasmussen encephalitis (one case) and poliodystrophy (one case). RESULTS: After VNS implantation, the stimulation amplitude was progressively increased and, after a mean interval of 47 days, a partial reduction of EPC and associated focal seizures was observed in all patients. After a mean follow-up of three years, one child stopped EPC, two presented short and rare episodes and in one patient 2-3 residual seizures per day was reported. In all cases, reduction of epileptic activity was associated with mild improvement of motor and cognitive abilities. No serious side effects were reported. CONCLUSION: VNS may be considered as an option for EPC when medical treatment fails and other more invasive neurosurgical options are not feasible.